Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice

Background and purpose: High resting heart rate is a predictor for total and cardiovascular mortality independent of other risk factors in patients with coronary artery disease. We tested the hypothesis that a reduction of resting heart rate with the cardiac pacemaker If current inhibitor ivabradine prevents the endothelial dysfunction associated with dyslipidaemia. Experimental approach: Three-month-old dyslipidaemic (DL) male mice expressing the human ApoB-100 were assigned or not (DL, n=16), to treatment for 3 months with ivabradine (10mgkg(-1) d(-1), n=17). Wild-type C57BI/6 mice (WT, n=15) were used as controls. Heart rate was measured at 3, 4.5 and 6 months. Dilatation to acetylcholine (ACh) of isolated cerebral and renal arteries was investigated at 6 months. Key results: Heart rate remained stable in anaesthetized WT mice, increased (25%, P < 0.05) with age in DL mice but was limited (11%, P < 0.05) by ivabradine. At 6 months, left ventricular maximal pressure was similar in all groups. The minimal and end-diastolic left ventricular pressures were increased (P < 0.05) in DL (10.2 +/- 1.0 and 18.7 +/- 1.4mmHg) compared to WT (-0.4 +/- 0.7 and 6.3 +/- 1.0mmHg) and reduced (P < 0.05) by ivabradine (4.2 +/- 1.3 and 11.5 +/- 1.5mmHg). ACh-induced maximal dilatation was impaired (P < 0.05) in renal and cerebral arteries isolated from DL compared to WT (56 +/- 7 versus 83 +/- 3% in renal arteries; 22 +/- 2 versus 42 +/- 2% in cerebral arteries). Ivabradine completely prevented (P < 0.05) this dysfunction in renal and cerebral arteries. Conclusions and implications: Selective heart rate reduction with ivabradine limits cardiac dysfunction and prevents the renovascular and cerebrovascular endothelial dysfunction associated with dyslipidaemia.